DESCRIPTION (Applicant's Abstract): Cocaine amphetamine, and other psychostimulant drugs, cause abuse and addiction by interacting with and altering certain neurochemical systems in brain. Recently, a neurochemical has been discovered which appears to be involved in cocaine's action. This neurochemical has been named CART (fro Cocaine and Amphetamine Regulated Transcript). The goal of this proposal is to clarify how CART peptides mediate or modulate the effects of cocaine and other psychostimulant drugs. A first step in this work is to show that injection of these peptides into the brain causes the same physiological effects that are caused by cocaine. In other words, CART peptides cause increased locomotor activity in rodents and reduced food intake. These are well known effects of the psychostimulant drugs themselves. In addition, we will look at the effects of these drugs at brain receptors; stimulation of physiologic receptors in brain is known to produce second messengers molecule such as cyclic AMP. Further, we will map the distribution of CART peptides in brain so as to fully understand where they are located and how they might influence the brain. We will also look at the effects of blocking their production and availability so as to obtain additional evidence about what they do, and we will prepare to make transgenic mice which either overproduce or have no CART peptide. These experiments will help us to understand how cocaine changes the brain, will show us how these new neurochemicals, the CART peptides, are involved in drug abuse, and may provide new strategies for developing medications to treat cocaine abuse and dependence.